Role of Gut Microbiota-Gut Hormone Axis in the ... · Role of Gut Microbiota-Gut Hormone Axis in the Pathophysiology of Functional Gastrointestinal Disorders Hirokazu Fukui,1* Xin

367ⓒ 2018 The Korean Society of Neurogastroenterology and Motility

J Neurogastroenterol Motil, Vol. 24 No. 3 July, 2018www.jnmjournal.org

Introduction

Although the pathogenesis of functional gastrointestinal dis-orders (FGIDs) is multifactorial, gastrointestinal (GI) dysmotility, and visceral hypersensitivity play a central role.1 Recently, much attention has been focused on gut microbiota, as it has become clear that alterations in the gut microenvironment are significantly involved in the pathophysiology of various diseases such as GI disease, metabolic syndrome, autoimmune disease, and nervous/endocrine system disorders.2 Gut microbiota have a complex influ-

ence on metabolism, nutrition and immune function in the host, and therefore disruption or alteration of the microbiota plays a pivotal role in GI inflammatory and/or FGIDs. Gut hormones also have central mediating roles in GI motility, appetite and body energy metabolism via the brain-gut axis, and thus also have pivotal involvement in FGIDs whose characteristic symptoms are closely associated with food intake. The present review provides a broad outline of interactions between the gut microbiota and gut hormone axis in relation to GI motility in the pathophysiology of FGIDs.

JNMJ Neurogastroenterol Motil, Vol. 24 No. 3 July, 2018pISSN: 2093-0879 eISSN: 2093-0887https://doi.org/10.5056/jnm18071

ReviewJournal of Neurogastroenterology and Motility

Received: April 10, 2018 Revised: None Accepted: May 21, 2018 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons. org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Correspondence: Hirokazu Fukui, MD, PhD Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, l-1, Mukogawa, Nishinomiya 663-8501, Japan Tel: +81-798-45-6662, Fax: +81-798-45-6661, E-mail: [email protected]

Role of Gut Microbiota-Gut Hormone Axis in the Pathophysiology of Functional Gastrointestinal Disorders

Hirokazu Fukui,1* Xin Xu,1,2 and Hiroto Miwa1 1Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Mukogawa, Nishinomiya, Japan; and 2Department of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin, China

Gut microbiota exert a pivotal influence on various functions including gastrointestinal (GI) motility, metabolism, nutrition, immunity, and the neuroendocrine system in the host. These effects are mediated by not only short-chain fatty acids produced by microbiota but also gut hormones and inflammatory signaling by enteroendocrine and immune cells under the influence of the microbiota. GI motility is orchestrated by the enteric nervous system and hormonal networks, and disturbance of GI motility plays an important role in the pathophysiology of functional gastrointestinal disorders (FGIDs). In this context, microbiota-associated mediators are considered to act on specific receptors, thus affecting the enteric nervous system and, subsequently, GI motility. Thus, the pathophysiology of FGIDs is based on alterations of the gut microbiota/gut hormone axis, which have crucial effects on GI motility.(J Neurogastroenterol Motil 2018;24:367-386)

Key WordsEnteric nervous system; Functional gastrointestinal disorders; Gastrointestinal hormones; Irritable bowel syndrome; Microbiome

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Hirokazu Fukui, et al

Journal of Neurogastroenterology and Motility 368

Role of Gut Hormones in the Pathophysiology of Functional Gastrointestinal Disorders

The motility of the GI tract is mediated by both neural and hormonal networks. Gut hormones are released from enteroendo-crine cells scattered along the GI tract (comprising fewer than 1% of all GI epithelial cells),3 which play prominent roles in the hor-monal networks during the interdigestive and postprandial periods. At present, more than 30 gut hormones have been isolated. Inter-estingly, the gut hormones that function in GI motility also affect appetite and body energy metabolism, suggesting that feeding be-havior and GI motility are cooperatively regulated by gut hormone secretion (Table 1).

Gut Hormones Affecting Interdigestive Motility

Motilin

Motilin, which is produced mainly by M cells in the duode-

num during the interdigestive period, promotes phase III activity of the migrating motor complex and gastric contraction. Erythro-mycin, a motilin receptor agonist, increases gastric emptying and not only alleviates gastroparesis but also mediates blood glucose control in diabetic patients.4 However, clinical use of erythromycin for dysmotility is thought to be difficult, as its continuous use causes dysbiosis of the gut flora.

Ghrelin

In 1999, ghrelin was isolated from the stomach as the endog-enous ligand of growth hormone secretagogue receptor 1a.5 Ghrelin is produced and secreted by X/A-like cells in the stomach (especially the fundus)5 and stimulates appetite and food intake.6 In addition, accumulating evidence has clarified that ghrelin stimulates both gastric motility and gastric acid secretion.7,8 Ghrelin stimulates GI motility by acting on not only neuropeptide Y, the preganglionic dorsal vagal complex and vagal afferent neurons, but also intrinsic cholinergic neurons in the GI tract,9-12 and these effects are remark-ably abolished by bilateral vagotomy.7

Table 1. Profile of Gut Hormones

Gut hormones Site of secretionEndocrine

cellsLocalization of

receptorsRoles in gastrointestinal motility

Motilin Duodenum, jejunum M-cells Vagal nerveCNS

Promotes phase III MMC activity Accelerates gastric contraction

Ghrelin Stomach, duodenum, jejunum X/A-cells Vagal nerveCNS

Suppresses motilin release Suppresses phase III MMC activity

CCK Duodenum, jejunum I-cells GastrointestineGallbladderVagal nerveEnteric neuronsCNS

Triggers gallbladder emptying Slows gastric emptyingAccelerates small intestinal transit

GIP Duodenum, jejunum K-cells Enteric neuronsCNS

Reduces phase III MMC activity Slows small intestinal transit

GLP-1 Ileum, colon L-cells Enteric neuronsImmune cellsCNS

Slows gastric emptyingSlows small intestinal transit Inhibits colonic transit

PYY Ileum, colon L-cells Enteric neuronsCNS

Slows gastric emptyingSlows small intestinal transit Inhibits colonic transit

Serotonin (5-HT) Whole GI tract EC cell Enteric neuronsMuscle cells Immune cellsVagal nerveCNS

Accelerates gastric emptying Accelerates gastric accommodation Initiates peristaltic reflex and propulsive motilityInduces slow excitatory postsynaptic potentialsTriggers colonic migrating motor complexes

CCK, cholecystokinin; GIP, glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide; GLP-1, glucagon-like peptide 1; PYY, peptide YY; 5-HT, 5-hydroxytryptamine; GI, gastrointestinal; EC, enterochromaffin; CNS, central nervous system; MMC, migrating motor complex.

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Gut Microbiota-Gut Hormone Axis in FGIDs

Vol. 24, No. 3 July, 2018 (367-386)

Gut Hormones Affecting Postprandial Motility

Cholecystokinin

Cholecystokinin (CCK) was discovered in jejunal extracts as a gallbladder contraction factor.13 CCK is abundantly synthesized in small-intestinal I-cells and cerebral neurons. In addition, CCK is expressed in various endocrine glands (pituitary, thyroid, pancreatic islets, adrenal, and testis), peripheral nerves and kidney.14 Indeed, CCK plays roles in not only digestive function (pancreatic enzyme secretion and gut motility) but also neurotransmission in the cere-bral and peripheral neuron systems.14 In the context of gut motility, it has been reported that exogenous CCK suppresses antral and duodenal motility,15 whereas CCK receptor antagonist accelerates gastric emptying.16 CCK is able to excite mucosal vagal afferent fi-bers in the stomach and regulate postprandial gastric emptying and satiation largely via the vagal pathway.17-19 On the other hand, small-intestinal transit time is shortened by stimulation with exogenous CCK, and prolonged by CCK receptor antagonist.20 In the colon, CCK administration does not affect human rectal motor function.21

Glucose-dependent insulinotropic polypeptide

Glucose-dependent insulinotropic polypeptide (GIP; also known as gastric inhibitory polypeptide) is produced mainly by K cells in the duodenum22 and stimulates insulin secretion as an in-cretin hormone in a glucose-dependent manner. In addition, GIP is likely to inhibit gastric acid secretion and gastric emptying in ani-mals, whereas these inhibitory effects remain unclear in humans.22 On the other hand, triglyceride disposal and adipose uptake of fatty acids may be important functions of GIP in humans.23

Glucagon-like peptide 1

Glucagon-like peptide 1 (GLP-1) is secreted predominantly from L cells in the ileum and colon and released as an incretin hor-mone in response to enteral nutrient exposure.24 GLP-1 as well as GIP stimulates insulin secretion and is rapidly degraded by dipep-tidylpeptidase-4 (DPP4).25 In this context, not only GLP-1 agonist but also the DPP4 inhibitor was developed as a therapeutic medi-cine for diabetes. Of note, GLP-1 also plays a role in postprandial GI motility. Studies using endogenous/exogenous GLP-1 and/or DPP4 inhibitors have revealed that GLP-1 slows gastric emptying and intestinal motility.26 Moreover, recent evidence has suggested that GLP-1 inhibits postprandial GI motility through the GLP-1 receptor at myenteric neurons, involving nitrergic and cAMP-dependent mechanisms.27,28

Peptide YY

Peptide YY (PYY) is secreted mainly from L cells in the ileum and colon29 and degraded by DPP4,30 similarly to GLP-1. Further-more, the function of PYY resembles that of GLP-1; thus, PYY is likely to suppress appetite, slow gastric emptying and inhibit small-intestinal motility.31 Endogenous PYY acts via neuronal Y2 recep-tors to inhibit colonic transit.32

Serotonin

Serotonin, also termed 5-hydroxytryptamine (5-HT), functions as both a neurotransmitter in the CNS and a local hormone in the GI tract. More than 90% of the body’s 5-HT is synthesized in the gut (approximately 90% of 5-HT originates from enterochromaf-fin (EC) cells and 10% from enteric neuron cells).33 Tryptophan hydroxylase-1 is the rate-limiting enzyme for biosynthesis of 5-HT, and serotonin reuptake transporter (SERT) terminates the actions of 5-HT by removing it from the interstitial space.34 5-HT has mo-tor function through interaction with neurons within the myenteric and submucosal plexuses, intrinsic and extrinsic sensory neurons, and EC cells. Among the 7 subtypes of serotonin receptors, 5-HT3

and 5-HT4 receptors have been most studied in the context of GI motility.35 5-HT released by mucosal mechanical and chemical stimuli is capable of inducing the mucosal peristaltic reflex, and hence propulsive peristalsis, and also affects the colonic migrating motor complexes.35

Dysregulation of Gut Hormone in Functional Gastrointestinal Disorders

FGIDs are defined by symptom-based diagnostic criteria that combine chronic or recurrent symptoms attributable to the GI tract in the absence of other pathologically based disorders. A number of factors are involved in the pathophysiology of FGIDs, including visceral sensitivity, GI motility, GI mucosal immunity, gut microbi-ota, and psychosocial stress in brain-gut interaction.1 Gut hormones have been proposed as key mediators of these factors in the brain-gut axis and are indeed involved in the development and/or exacer-bation of FGID symptoms (Tables 2 and 3), as described below.

Functional dyspepsia

Functional dyspepsia (FD) is a heterogeneous disorder associ-ated with abnormalities of gut motor function, including initially accelerated or delayed gastric emptying, impaired proximal gastric relaxation, increased perception of gastric distension, and disordered antro-duodenal motility.36

370



Tabl

e 2.

Dys

regu

latio

n of

Gut

Hor

mon

es in

Fun

ctio

nal D

yspe

psia

Gut

ho

rmon

ePu

blish

ed

year

Clin

ical

evi

denc

es fo

r gut

hor

mon

e in

FD

Ref

eren

ceN

o.

Mot

ilin

2000

AB

T-22

9 (m

otili

n ag

onist

) doe

s not

relie

ve th

e sy

mpt

oms i

n F

D p

atie

nts.

3820

05E

xoge

nous

mot

ilin

stim

ulat

ion

inhi

bits

pro

xim

al g

astr

ic a

ccom

mod

atio

n in

FD

pat

ient

s.36

2008

Cam

icin

al a

ccel

erat

es g

astr

ic e

mpt

ying

(35-

60%

) in

patie

nts w

ith g

astr

opar

esis.

4020

16M

otili

n re

cept

or a

goni

st (c

amic

inal

; GSK

9620

40) a

ccel

erat

es g

astr

ic e

mpt

ying

and

incr

ease

s glu

cose

abs

orpt

ion

in fe

ed-in

tole

rant

crit

ical

ly il

l pa

tient

s.39

Ghr

elin

2004

The

pla

sm g

hrel

in c

once

ntra

tion

may

be

decr

ease

d in

acc

orda

nce

with

the

prog

ress

ion

of g

astr

ic a

trop

hy d

ue to

H. p

ylor

i inf

ectio

n.45

2005

Pla

sma

acyl

ated

ghr

elin

leve

ls ar

e co

rrel

ated

with

sym

ptom

scor

e in

FD

pat

ient

s.43

2006

Ghr

elin

, a n

ovel

app

etite

-pro

mot

ing

gast

roin

test

inal

pep

tide

that

also

pro

mot

es g

astr

ic m

otili

ty o

r bas

al a

cid

secr

etio

n m

ay b

e a

ther

apeu

tic ta

rget

fo

r FD

trea

tmen

t.44

2007

Fast

ing

desa

cyl a

nd to

tal g

hrel

in le

vels

are

signi

fican

tly lo

wer

in F

D p

atie

nts t

han

in c

ontr

ols,

but a

ctiv

e gh

relin

leve

ls ar

e sim

ilar b

etw

een

2 gr

oups

in b

oth

fast

ing

and

post

pran

dial

per

iods

. 41

2008

Ghr

elin

trea

tmen

t ten

ds to

incr

ease

dai

ly fo

od in

take

in F

D p

atie

nts.

4620

09A

cyla

ted

ghre

lin le

vels

are

signi

fican

tly lo

wer

in N

ER

D a

nd P

DS

patie

nts t

han

in h

ealth

y vo

lunt

eers

.17

3A

bnor

mal

ly lo

w p

repr

andi

al g

hrel

in le

vels

and

abse

nce

of si

gnifi

cant

pos

tpra

ndia

l dec

reas

e of

ghr

elin

leve

ls ar

e pr

esen

t in

a su

bset

of d

ysm

otili

ty-

like

FD

pat

ient

s.42

2013

The

pre

prog

hrel

in 3

056T

T g

enot

ype

is sig

nific

antly

ass

ocia

ted

with

the

acyl

ated

ghr

elin

leve

ls an

d th

e fe

elin

g of

hun

ger i

n H

. pyl

ori-

nega

tive

FD

pat

ient

s.17

4

2015

The

seru

m g

hrel

in le

vel 3

0 m

inut

es a

fter b

reak

fast

is si

gnifi

cant

ly h

ighe

r in

dysp

epsia

pat

ient

s tha

n in

con

trol

s.17

5F

D-P

DS

is as

soci

ated

with

low

er fa

stin

g an

d m

axim

um a

cyl g

hrel

in c

once

ntra

tions

and

dam

pene

d ac

yl g

hrel

in fl

ux.

176

CC

K19

94F

D p

atie

nts w

ith C

CK

-8 st

imul

atio

n sh

ow st

rong

er sy

mpt

oms o

f dys

peps

ia c

ompa

red

with

hea

lthy

cont

rol.

4820

08Fa

stin

g an

d po

stpr

andi

al p

lasm

a C

CK

is g

reat

er in

FD

pat

ient

s.47

2014

Follo

win

g lip

id in

fusio

n, th

e m

ean

muc

osal

CC

K c

once

ntra

tion

is lo

wer

in F

D p

atie

nts c

ompa

red

with

hea

lthy

volu

ntee

rs.

177

GIP

and

GL

P-1

20

14In

crea

sed

sens

itivi

ty to

ent

eral

dex

tros

e an

d lip

id in

fusio

ns is

ass

ocia

ted

with

gre

ater

pla

sma

GIP

and

GL

P-1

conc

entr

atio

ns in

FD

. 51

2016

GL

P-1

conc

entr

atio

n is

simila

r in

FD

pat

ient

s and

con

trol

s, bu

t pos

tpra

ndia

l GL

P-1

secr

etio

n m

ay c

orre

late

with

nau

sea

in F

D p

atie

nts.

52P

YY

2008

Fast

ing

and

post

pran

dial

PY

Y a

re lo

wer

in F

D p

atie

nts t

han

in h

ealth

y su

bjec

ts.

4720

14P

YY

con

cent

ratio

ns in

resp

onse

to d

extr

ose

and

lipid

infu

sions

are

hig

her i

n F

D p

atie

nts w

ith im

paire

d gl

ucos

e to

lera

nce.

51Se

roto

nin

(5-H

T)

2011

Sero

toni

n re

cept

or 3

A p

olym

orph

ism H

TR

3A c

.-42T

is a

ssoc

iate

d w

ith se

vere

dys

peps

ia.

54Se

roto

nin

tran

spor

ter g

ene

poly

mor

phism

may

be

asso

ciat

ed w

ith fu

nctio

nal d

yspe

psia

in a

Jap

anes

e po

pula

tion.

5520

13Pa

tient

s with

FD

hav

e lo

wer

bas

al a

nd p

ostp

rand

ial p

lasm

a le

vels

of se

roto

nin.

56

FD

, fun

ctio

nal d

yspe

psia

; H. p

ylor

i, H

elic

obac

ter

pylo

ri; N

ER

D, n

on-e

rosiv

e re

flux

dise

ase;

PD

S, p

ostp

rand

ial d

istre

ss s

yndr

ome;

CC

K, c

hole

cyst

okin

in; G

IP, g

luco

se-d

epen

dent

insu

linot

ropi

c po

lype

ptid

e/ga

stric

inhi

bito

ry p

olyp

eptid

e; G

LP-

1, g

luca

gon-

like

pept

ide

1; P

YY,

pep

tide

YY;

5-H

T, 5

-hyd

roxy

tryp

tam

ine.

371371


Vol. 24, No. 3 July, 2018 (367-386)

Motilin and ghrelin, which may accelerate gastric emptying, are potential pathogenetic factors targets for clinical management of FD. For instance, although fasting motilin levels in FD patients do not differ from those in healthy subjects, exogenous motilin stimula-tion produces greater inhibition of proximal gastric accommodation in FD patients.36 In connection with gastric emptying, mitemcinal (a motilin receptor agonist) and ABT-229 (a motilin agonist) have

been administered to patients with gastroparesis or FD, but it is still unclear whether they relieve symptoms such as abdominal satiety and pain in patients with FD.37,38 Another motilin receptor agonist (camicinal; GSK962040) has been developed and used in a phase II trial for critically ill patients with food intolerance.39 Camicinal has been shown to accelerate gastric emptying by 35-60% in pa-tients with gastroparesis,40 and therefore further clinical studies of

Table 3. Dysregulation of Gut Hormones in Irritable Bowel Syndrome

Gut hormone

Pub-lishedyear

Clinical evidences for gut hormone in IBSReference

No.

Motilin 1985 Circulating motilin is positively correlated with symptoms in functional bowel disorders. 591996 The IBS patients have reduced motilin secretion after both water intake and the fat meal. 602005 Higher motilin levels are observed in IBS in both interdigestive and postprandial periods. 61

Ghrelin 2009 The number of ghrelin-positive cells is increased in IBS-D patients. 66The low densities of ghrelin cell is found in IBS-C patients. 66

CCK 2006 IBS patients have increased fasting and postprandial plasma levels of CCK 1782010 Post-infectious IBS patients have increased numbers of CCK cells in the duodenum. 702015 The densities of duodenal CCK cells are significantly lower in patients with IBS-D. 69

GIP 2015 The GIP cell density is significantly reduced in IBS-C. 69GLP-1 2009 GLP-1 analog (ROSE-010) relieves acute pain attacks in IBS patients. 76

2012 GLP-1 analog (ROSE-010) delays gastric emptying of solids in IBS-C patients. 752014 Exogenous glucagon-like peptide 1 reduces contractions in human colon circular muscle. 722017 Decreased serum GLP-1 correlates with abdominal pain in patients with IBS-C 71

PYY 2010 The increased PYY is observed in IBS-C patients whose colonic transit is delayed. 802014 The expression of PYY is increased in the ileum in patients with IBS-C. 79

The densities of PYY cells is significantly lower in IBS patients than controls. 81PYY expression is higher in the colon in post-infectious IBS. 82

2017 PYY cell density is increased in IBS-C relative to controls. 94Serotonin (5-HT)

2003 Plasma serotonin levels is increased in IBS-D. 912006 Postprandial plasma serotonin level is decreased in IBS-C. 902007 IBS patients have elevated concentrations of platelet depleted plasma 5-HT under fasting and fed conditions

compared with controls.87

2009 Fasting and postprandial plasma 5-HT concentrations are significantly higher in IBS patients. 862010 In the IBS samples, higher 5-HT content and lower SERT mRNA are detected as compared with controls. 179

Post-infectious IBS patients have significantly lower plasma 5-HIAA. 702011 Compared with healthy controls, patients with IBS show a significant increase in 5-HT-positive cell counts and

5-HT release.92

2012 The frequency of SLC6A4-polymorphism and higher levels of 5-HT are significantly associated with IBS 180Serotonin and PYY cell densities are reduced in the colon of IBS patients. 181

2014 The intensity of serotonin transporter immunoreactivity is increased in the ileum of patients with IBS. 182The density of the serotonin-immunoreactive cells is significantly decreased in the IBS-M patients and in-

creased in the IBS-C patients relative to the controls.93

2016 The 5-HIAA concentrations and 5-HT acetic acid /5-HT ratio are significantly lower in IBS compared to HC. 882017 The densities of serotonin cells are reduced in IBS patients. 94

IBS patients show increased 5-HT compared to healthy volunteers. 85

IBS, irritable bowel syndrome; IBS-D, irritable bowel syndrome with diarrhea; IBS-C, irritable bowel syndrome with constipation; CCK, cholecystokinin; GIP, glu-cose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide; GLP-1, glucagon-like peptide 1; PYY, peptide YY; 5-HT, 5-hydroxytryptamine; SERT, serotonin reuptake transporter; 5-HIAA, 5-hydroxyindole acetic acid.

372



camicinal may be justified in patients with FD.As for ghrelin, a few studies have reported that the level of

ghrelin in plasma is decreased in FD patients,41,42 whereas others have indicated that it is elevated in such patients and related to the severity of their symptoms,43,44 and thus opinion is still divided. The plasma ghrelin concentration may decrease in accordance with the progression of gastric atrophy due to Helicobacter pylori infection.45 In addition to gastric atrophy, obesity and stress also affect the plasma ghrelin level, thus complicating our understanding of how ghrelin is involved in the pathophysiology of FD. Ghrelin may be a potentially promising therapeutic agent for FD, and Akamizu et al46 have reported that ghrelin administration improves appetite in affected patients. However, as their study was preliminary and did not include a placebo group, further large scale clinical studies in-cluding FD symptoms and GI motility assessments will be needed.

In patients with FD, both fasting and postprandial plasma CCK concentrations are higher. Interestingly, intake of a high-fat diet increases the CCK level significantly and is related to the sever-ity of nausea, suggesting that fat diet-associated CCK is involved in the development of FD symptoms.47 Furthermore, Chua et al48 have reported that FD patients stimulated with CCK-8 showed more severe symptoms of dyspepsia than healthy controls, sug-gesting that FD patients are hypersensitive to CCK stimulation. Also, as CCK promotes serotonin secretion in the hypothalamus,49 FD patients likely have central nervous system hypersensitivity to serotonin.50 Thus, postprandial CCK may affect serotonin signaling in the central nervous system in FD patients and participate in the development of their symptoms.

The hormone incretin plays a role in not only postprandial glu-cose metabolism but also GI motility, strongly suggesting significant involvement of incretin in the food-intake-associated pathophysiol-ogy of FD. Although the fasting plasma GIP and GLP-1 concen-trations do not differ between FD patients and healthy controls, FD patients show hypersensitive responses to lipid infusion into the duodenum.51 Moreover, FD patients with severe symptoms show higher GIP and GLP-1 levels in response to lipid stimulation, sup-porting the contention that incretin mediates increased intestinal sensitivity to nutrients in FD. Witte et al52 have also reported that although the GLP-1 concentration is altered in FD, postprandial GLP-1 secretion correlates with nausea in affected patients. GIP and GLP-1 may be important targets for the treatment of not only diabetes/metabolic syndrome but also FD, and therefore further clinical studies should be encouraged.

PYY as well as GLP-1 is known to act as an “ileal brake” by suppressing GI motility, implying its pathophysiologic involvement

in FD. In this connection, it is tempting to speculate that plasma PYY might be increased in FD patients. However, Pilichiewicz et al47 have reported that both the fasting and postprandial PYY levels are lower in FD patients than in healthy subjects, and Bharucha et al51 have found no difference between the two. Thus, although plasma PYY is not increased in patients with FD, this issue requires further investigation.

Data on 5-HT abnormalities are relatively fewer for FD than for IBS patients. It has been reported that 5-HT4 receptor agonists may improve symptoms of dyspepsia, particularly in patients with delayed gastric emptying.53 Previous studies have shown that 5-HT receptor 3A polymorphism54 and SERT gene polymorphism are associated with dyspeptic symptoms.55 Cheung et al56 recently showed that low levels of baseline and postprandial 5-HT are as-sociated with early satiation, lower calorie intake, and more severe postprandial dyspeptic symptoms in FD patients.

Irritable bowel syndrome

Irritable bowel syndrome (IBS) is characterized by symptoms such as abdominal pain or discomfort, bloating, and stool irregu-larities, without any structural or organic lesions.57 Many factors are involved in the pathogenesis of IBS, and indeed gut hormones are key players, as described below.

The levels of motilin reported in IBS patients have been con-flicting, various studies indicating that they are higher,58 similar to,59 or reduced60 in comparison with healthy controls. Although dysmotility and visceral hypersensitivity are thought to play a cru-cial role in the pathophysiology of IBS, a high level of motilin may not reflect alteration of GI motility in IBS patients.61 In addition, exogenous motilin does not affect rectal sensation, at least in healthy volunteers.62 These findings suggest that alterations of the motilin level may be a consequence rather than a cause of IBS. The effect of erythromycin (a motilin receptor agonist) on colonic motility is also controversial; some studies have demonstrated that erythromycin accelerates the intestinal and/or colonic transit time,63,64 whereas oth-ers have not confirmed this.64,65

It is interesting that the ghrelin cell density in the gastric oxyntic mucosa is altered in patients with IBS. On the other hand, since IBS and FD frequently overlap, it is not unlikely that endocrine cells may be altered in the upper GI in IBS. Although evidence is still insufficient, it has been reported that ghrelin cell density is decreased in patients with IBS with constipation (IBS-C).66 This finding may not be surprising because the delay in intestinal transit time can be explained by inhibition of motility-promoting ghrelin. In contrast, ghrelin-positive cells are increased in patients with IBS

373373


Vol. 24, No. 3 July, 2018 (367-386)

with diarrhea (IBS-D),66 supporting the fact that such patients show rapid gastric emptying.67 However, gastric emptying in IBS is still controversial.68

El-Salhy M et al69 have shown that the densities of CCK are reduced in the duodenum of IBS-D patients, whereas they are not altered in IBS-C patients. In IBS-D patients, reduction of CCK may be involved in the rapid gastric emptying.67 A subgroup of IBS patients are known to have a history of infectious colitis, and show an increased number of CCK-positive cells.70 Furthermore, the plas-ma level of CCK is likely increased in the fasting and postprandial periods in IBS patients,70 similarly to the situation in FD patients.47 In contrast to the stomach, CCK stimulates intestinal motility, and therefore high CCK levels may be associated with the diarrhea seen in post-infectious IBS.

The density of duodenal endocrine cells differs between healthy controls and IBS patients. Indeed, GIP cell density is significantly decreased in both IBS-C and IBS-D,69 but other information on GIP in IBS is sparse. Clinical trials of a GLP-1 analog have been performed in IBS patients. Li et al71 have shown that the serum GLP-1 level was significantly decreased in IBS-C patients and neg-atively correlated with the severity of abdominal pain/discomfort. However, this seems paradoxical because GLP-1 inhibits intestinal motility and reduction of GLP-1 would lead to acceleration of GI motility. In this connection, opinion regarding the action of GLP-1 on colonic motility is still divided, both inhibitory and stimulatory effects having been reported.72-74 In a placebo-controlled trial, Ca-milleri et al75 showed that a GLP-1 receptor agonist, ROSE-010, improved colonic transit time in IBS-C patients, and Hellström et al76 found that ROSE-010 administration relieved acute pain in patients with IBS. Additionally, the GLP-1 receptor agonist also decreases visceral sensitivity and accelerates colonic transit via the central corticotropin-releasing factor and peripheral vagal pathways, although these findings were obtained in animal experiments.77,78

The expression of PYY is increased in the ileum of patients with IBS-C.79 As PYY inhibits colonic transit, it seems logical that IBS-C patients with delayed colonic transit show increased expres-sion of PYY.80 However, the number of PYY-positive endocrine cells is smaller in the colon and rectum in both IBS-D and IBS-C patients,79,81 and PYY expression is high in the colon of patients with post-infectious IBS.82 These discrepancies may reflect the complicated pathophysiology of IBS. In fact, it is known that IBS patients switch from one subtype to another at least once yearly,83,84 probably as a result of the complex behavior of their enteroendo-crine cells.

Data on 5-HT in IBS patients have been conflicting (Table 2).

Some studies have reported that in both fasting and postprandial states, the plasma 5-HT level is increased in IBS patients relative to healthy volunteers,85-87 whereas others have found no differences in the plasma 5-HT level between the 2 groups.88 When IBS patients are subdivided, the plasma serotonin level is decreased in those with IBS-C89,90 and increased in those with IBS-D.90,91 A few histological studies have demonstrated that the number of 5-HT-positive cells is increased in IBS (especially post-infectious IBS),89,92 although con-flicting data have also been reported.93,94 Genetic analyses of SERT polymorphism have also yielded mixed results.95-97 However, such discrepancies are not surprising because 5-HT is not the only factor operating in the development of IBS. On the other hand, the recep-tors for 5-HT are widely expressed in various types of cells includ-ing neurons and smooth muscle cells,35 and indeed 5-HT signaling is involved in GI motility and the development of IBS-related symptoms. In this context, it is noteworthy that release of 5-HT from the colonic mucosa correlated with the severity of abdominal pain in IBS patients.92

Role of Gut Microbiota in the Pathophysiology of Functional Gastrointestinal Disorders

The human microbiota comprises approximately 1200 dif-ferent bacterial species whose number (1013-1014) in the gut is 10 times greater than the total number of cells in the human body.2 Gut microbiota exert a marked influence on host physiology includ-ing metabolism, nutrition, and immune function, and therefore, its disruption or alteration has been linked with GI inflammatory and functional disease.98 It has become increasingly evident that host-gut microbial interactions have an extremely important role in the pathogenesis of FGIDs (Table 4), especially IBS.99 Recent advanc-es in sequencing technology have revealed that the profile of gut microbiota differs between patients with IBS and healthy subjects, and this has promoted researchers to investigate the role of the gut microbiota in IBS.

Gut Microbiota Production of Serotonin and SCFAEvolutionarily-oriented studies have shown that many enzymes

involved in human hormone metabolism have evolved through gene transfer from bacteria.100 Interestingly, serotonin and other hormones such as epinephrine, norepinephrine and dopamine are produced and/or secreted from specific bacterial strains.101 Further-more, it has been revealed that microorganisms harbor hormone receptors,102 suggesting that gut hormones act as possible mediators

374



of communication between the host and gut microbiota. Depending on the substrates (amino acids, lipids or carbohy-

drates) present in the intestinal lumen, gut microbiota can generate specific metabolites. Short-chain fatty acids (SCFAs) are produced by microbiota in the ileum and colon from carbohydrates with low digestibility (resistant starch and soluble oligo- and polysaccha-rides). The main components of SCFAs in the human colon are acetate (2-carbon), propionate (3-carbon), and butyrate (4-carbon), at a ratio of about 3:1:1.103,104 Butyrate is considered a major energy source for the colonic epithelium. Propionate, entering the portal circle, is primarily utilized for gluconeogenesis in the liver. Conse-quently, SCFAs in plasma are largely acetate.105,106 Approximately 95% of the produced SCFAs are rapidly absorbed by colonocytes in the large intestine while the remaining 5% are secreted in the stools.107

Short-chain Fatty Acids as a Mediator between Gut Microbiota and Endocrine Cells

SCFAs serve as not only an important energy source but also chemical messengers or signaling molecules for various types of cells. GPR41 and GPR43, which are classified as G protein-cou-pled receptors and known as free fatty acid receptor (FFAR)3 and FFAR2, respectively, have recently been identified as receptors for SCFAs. Since these receptors are expressed in a variety of cell types, including colonic endocrine L cells, mucosal mast cells, adipose tis-sue, neutrophils, and monocytes, activation of these receptors may elicit distinct functions in various fields. Both GPR41 and GPR43 exhibit coupling to the Gi/o family and inhibit cAMP production, whereas GPR43, but not GPR41, also couples efficiently through the Gq protein family.108

In the ileum and colon, GPR41 and GPR43 are expressed in enteroendocrine L-cells that secrete GLP-1 and PYY.109 Therefore, it had been expected that SCFA would promote GLP-1 and PYY secretion by activating these GPRs, and indeed several in vivo studies have demonstrated that intraluminal injection of SCFAs in-duced the release of PYY and GLP-1 into the circulating blood.110 Furthermore, in vitro studies have shown that activation of GPR43 by SCFAs promotes GLP-1 secretion111 and PYY expression112 in enteroendocrine cells. On the other hand, individual GPR41- or GPR43-deficient mice show low GLP-1 release in response to SCFA stimulation, indicating that both GPR41 and GPR43 are involved in SCFA-evoked GLP-1 release.111 These findings strongly suggest that SCFA signaling to GPR41 and GPR43 on L cells is crucial for controlling the levels of GLP-1 and PYY, thus playing a pivotal role in the “ileal brake.” However, in GF mice,

Wichmann et al113 have demonstrated that total SCFA in the cecal content is decreased whereas the plasma GLP-1 level is increased. They showed that colonization of GF mice with microbiota or treat-ment with SCFAs reduced the expression of GLP-1 in the colon.113 Although these findings are difficult to reconcile, the explanation proposed is that GF mice are deprived of SCFAs produced by gut microbiota and serve as an important energy source for colonocytes. Subsequently, in response to this insufficiency of available energy in the colon, the GLP-1 level is increased to slow intestinal transit. In this context, GPRs may act as sensors of the amount of SCFA rather than being receivers of SCFA signaling.

SCFAs may be involved in the production of not only GLP-1 and PYY, but also other gut hormones such as 5-HT, GIP, ghrelin, and CKK. Histological studies have clarified that GPR43 is co-expressed with 5-HT,114 and that SCFAs stimulate the release of 5-HT by EC cells in the colonic mucosa.115 On the other hand, GPR40 and/or GPR120 are co-localized in cells expressing GIP, GLP-1, PYY, CCK, ghrelin, or 5HT,116-118 although their ligands are predominantly medium- to long-chain fatty acids.119 Taken to-gether, the available data suggest that GPRs are key tools involved in the interaction between endocrine cells and fatty acids produced from food and gut microbiota.

Alterations of Gut Microbiota in the Pathophysiology of Functional Gastrointestinal Disorders

The Rome Foundation has recently provided an excellent over-view of the importance of microbiota in health and disease, espe-cially functional bowel diseases.99 It is widely accepted that GI infec-tions caused by bacteria, viruses, or parasites are strong risk factors for the development of FGIDs.120 With regard to the association between bacterial infection and FD, almost all current knowledge is based on H. pylori infection. H. pylori causes chronic atrophic gas-tritis, gastroduodenal ulcers and gastric cancers, suggesting a close involvement in the development of organic disease. In this context, whether or not patients with H. pylori infection should be excluded from the category of FD has been discussed. However, possible pathogenetic concepts to explain the link between H. pylori infec-tion and dyspeptic symptoms have been positively incorporated into the recent Rome IV classification121 and management guidelines for H. pylori infection.122 In response to the recent focus on gut microbiota and FGIDs, several studies have begun to investigate the gastric microbiota in FD patients. For instance, as dysbiosis has been observed in the gastric fluid of patients with FD,123 it has been suggested that normalization of the gastric microbiota by probiotics

375375


Vol. 24, No. 3 July, 2018 (367-386)

Tabl

e 4.

Dat

a by

Mic

robi

ota

Ana

lyse

s in

Func

tiona

l Gas

troi

ntes

tinal

Diso

rder

s Pat

ient

s

Publ

ished

ye

arM

ain

findi

ngs o

f mic

robi

ota

anal

yses

in F

GID

pat

ient

sR

efer

ence

No.

Func

tiona

l dys

peps

ia20

16T

he o

vera

ll st

ruct

ure

of th

e ba

cter

ial c

omm

unity

and

the

abun

danc

e of

gen

us P

revo

tella

in th

e ga

stric

flui

d of

the

FD

pat

ient

s wer

e sig

nific

antly

diff

eren

t fro

m

thos

e in

the

HC

.12

3

2017

Alte

ratio

n in

the

gast

ric fl

uid

mic

robi

ota

char

acte

rized

by

Bac

tero

idet

es >

Pro

teob

acte

ria a

bund

ance

and

the

abse

nce

of A

cido

bact

eria

was

foun

d in

the

gast

ric

fluid

of p

atie

nts w

ith F

D.

124

Irrit

able

bow

el sy

ndro

me

1994

IBS

is fr

eque

ntly

occ

urre

d in

pat

ient

s afte

r Sal

mon

ella

-indu

ced

ente

ritis.

125

2005

Low

er a

mou

nts o

f Lac

toba

cillu

s sp

p. w

ere

pres

ent i

n th

e sa

mpl

es o

f IB

S-D

pat

ient

s whe

reas

IB

S-C

pat

ient

s car

ried

incr

ease

d am

ount

s of V

eillo

nella

spp

.18

320

07Si

gnifi

cant

diff

eren

ces b

etw

een

IBS

and

cont

rol w

ere

foun

d in

seve

ral b

acte

rial g

ener

a w

hich

bel

ong

to C

opro

cocc

us, C

ollin

sella

, and

Cop

roba

cillu

s.18

420

09T

he m

icro

bial

com

mun

ities

of I

BS-

D p

atie

nts w

ere

enric

hed

in P

rote

obac

teria

and

Firm

icut

es, b

ut re

duce

d in

the

num

ber o

f Act

inob

acte

ria a

nd B

acte

roid

etes

co

mpa

red

to H

C.

185

2010

IBS

patie

nts s

how

ed si

gnifi

cant

ly h

ighe

r cou

nts o

f Vei

llone

lla a

nd L

acto

baci

llus

than

con

trol

s.18

6A

sign

ifica

nt d

iffer

ence

bet

wee

n IB

S an

d H

C w

as in

dica

ted

with

sign

ifica

ntly

mor

e va

riatio

n in

the

gut m

icro

biot

a of

hea

lthy

volu

ntee

rs th

an th

at o

f IB

S pa

tient

s.18

7Q

uant

itativ

e P

CR

ana

lysis

dem

onst

rate

d a

signi

fican

t 3.6

fold

incr

ease

in c

once

ntra

tions

of f

ecal

Lac

toba

cillu

s sp

ecie

s bet

wee

n IB

S-D

pat

ient

s and

HC

.18

820

11Ps

eudo

mon

as a

erug

inos

a w

as si

gnifi

cant

ly m

ore

abun

dant

in fa

eces

of I

BS

patie

nts t

han

in fa

eces

of h

ealth

y su

bjec

ts.

189

The

mic

robi

ota

of I

BS

had

a 2-

fold

incr

ease

d ra

tio o

f the

Firm

icut

es to

Bac

tero

idet

es c

ompa

red

with

con

trol

s.13

0M

icro

biom

es a

ssoc

iate

d w

ith p

edia

tric

IB

S w

ere

char

acte

rized

by

a sig

nific

antly

gre

ater

per

cent

age

of th

e cl

ass γ

-pro

teob

acte

ria; o

ne p

rom

inen

t com

pone

nt o

f thi

s gr

oup

was

Hae

mop

hilu

s par

ainf

luen

zae.

190

The

bio

dive

rsity

of m

icro

bes w

ithin

feca

l sam

ples

from

IB

S-D

pat

ient

s is l

ower

(1.2

-fol

d) th

an th

at fr

om H

C.

191

2012

IBS

mic

robi

ota

show

ed a

n in

crea

se in

rela

tive

abun

danc

e of

lact

obac

illi,

B. c

ereu

s an

d B

. cla

usii,

bifi

doba

cter

ia, C

lost

ridiu

m c

lust

er I

X a

nd E

. rec

tale

, and

a d

e-cr

ease

in a

bund

ance

of B

acte

roid

es/P

revo

tella

gro

up a

nd V

eillo

nella

gen

us.

192

IBS-

D p

atie

nts h

ad si

gnifi

cant

ly h

ighe

r lev

els o

f Ent

erob

acte

riace

ae a

nd lo

wer

leve

ls of

Fec

alib

acte

rium

gen

era

com

pare

d to

HC

.19

3A

n in

crea

sed

Firm

icut

es:B

acte

roid

etes

ratio

bes

t cha

ract

erise

s tho

se I

BS

subj

ects

who

diff

er fr

om n

orm

al p

opul

atio

ns.

194

Bifi

doba

cter

ia w

ere

low

er in

the

IBS-

D g

roup

than

in th

e IB

S-C

gro

up a

nd c

ontr

ols.

The

max

imum

num

ber o

f sto

ols p

er d

ay n

egat

ivel

y co

rrel

ated

with

the

num

-be

r of m

ucos

a-as

soci

ated

Bifi

doba

cter

ia a

nd L

acto

baci

lli in

IB

S.19

5

2013

The

sens

itivi

ty to

col

onic

dist

ensio

n of

IB

S pa

tient

s can

be

tran

sfer

red

to ra

ts b

y th

e fe

cal m

icro

biot

a.13

120

14Se

vera

l mem

bers

of B

acte

roid

etes

phy

lum

wer

e in

crea

sed

12-f

old

in P

I-IB

S pa

tient

s, w

hile

HC

had

35-

fold

mor

e un

cultu

red

Clo

strid

ia.

196

376



Tabl

e 4.

Con

tinue

d

Publ

ished

ye

arM

ain

findi

ngs o

f mic

robi

ota

anal

yses

in F

GID

pat

ient

sR

efer

ence

No.

2015

Diff

eren

ces i

n th

e m

ucos

al-a

ssoc

iate

d m

icro

biot

a be

twee

n he

alth

y in

divi

dual

s and

IB

S pa

tient

s are

min

imal

(one

bac

teria

l gro

up) c

ompa

red

to d

iffer

ence

s in

the

faec

al m

icro

biot

a of

bot

h gr

oups

(53

bact

eria

l gro

ups)

. 19

7

Valid

atio

n co

nfirm

s dys

bios

is w

as d

etec

ted

in 7

3% o

f IB

S pa

tient

s, 70

% o

f tre

atm

ent-

naïv

e IB

D p

atie

nts a

nd 8

0% o

f IB

D p

atie

nts i

n re

miss

ion,

vs.

16%

of h

ealth

y in

divi

dual

s.19

8

16S

rDN

A se

quen

cing

con

firm

ed m

icro

bial

ove

rgro

wth

and

its d

iver

sity-

redu

ctio

n in

the

smal

l bow

el o

f IB

S pa

tient

s.19

9N

umbe

r of B

acte

roid

es th

etai

otam

icro

n an

d Ps

eudo

mon

as a

erug

inos

a w

ere

high

er a

mon

g IB

S pa

tient

s. N

umbe

r of B

acte

roid

es th

etai

otam

icro

n an

d se

gmen

ted

filam

ento

us b

acte

ria (S

FB

) was

hig

her a

mon

g IB

S-D

than

IB

S-C

. Abd

omin

al d

isten

sion

was

ass

ocia

ted

with

hig

her n

umbe

r of B

acte

roid

es th

etai

otam

icro

n,

Clo

strid

ium

coc

coid

es, P

. aer

ugin

osa,

SF

B, a

nd G

ram

-neg

ativ

e ba

cter

ia (G

NB

); b

loat

ing

was

ass

ocia

ted

with

Clo

strid

ium

coc

coid

es a

nd G

NB

.

200

Feca

l mic

robi

ota

com

posit

ion

of P

I-IB

S pa

tient

s diff

ered

sign

ifica

ntly

from

bot

h ge

nera

l IB

S pa

tient

s and

HC

. Bot

h m

ucos

al a

nd fe

cal m

icro

bial

div

ersit

y w

ere

redu

ced

in P

I-IB

S co

mpa

red

to H

C.

201

2016

Hig

her a

bund

ance

of c

olon

ic V

eillo

nella

ceae

and

smal

l int

estin

al P

revo

tella

ceae

, and

low

er a

mou

nt o

f ora

l cav

ity n

orm

al fl

ora

in p

roxi

mal

smal

l int

estin

e w

ere

foun

d in

IB

S pa

tient

s.20

2

Bac

tero

idet

es w

as p

redo

min

ant i

n fe

cal s

ampl

es fr

om H

C a

nd I

BS-

D a

nd I

BS-

M su

bjec

ts, w

here

as F

irmic

utes

was

pre

dom

inan

t in

sam

ples

from

IB

S-C

subj

ects

. Sp

ecie

s ric

hnes

s, bu

t not

com

mun

ity d

iver

sity,

diffe

rent

iate

d al

l IB

S pa

tient

s fro

m H

C.

203

In I

BS-

C p

atie

nts,

Bac

tero

ides

, Ros

ebur

ia-E

ubac

teriu

m re

ctal

e an

d B

ifido

bact

eriu

m w

ere

decr

ease

d, a

nd E

nter

obac

teria

ceae

, Des

ulfo

vibr

io sp

., an

d m

ainl

y A

k -ke

rman

sia m

ucin

iphi

la w

ere

incr

ease

d co

mpa

red

to h

ealth

y in

divi

dual

s. 20

4

2017

Mic

e re

ceiv

ing

the

IBS-

D fe

cal m

icro

biot

a, e

xhib

ited

fast

er g

astr

oint

estin

al tr

ansit

, int

estin

al b

arrie

r dys

func

tion,

inna

te im

mun

e ac

tivat

ion,

and

anx

iety

-like

be -

havi

or.

205

Dow

n-re

gula

tion

of b

acte

rial c

olon

izat

ion

incl

udin

g L

acto

baci

llus,

Bifi

doba

cter

ium

, and

F. p

raus

nitz

ii w

as o

bser

ved

in I

BS

patie

nts,

part

icul

arly

in I

BS-

D.

206

IBS

sym

ptom

seve

rity

was

ass

ocia

ted

nega

tivel

y w

ith m

icro

bial

rich

ness

, exh

aled

CH

4, p

rese

nce

of m

etha

noge

ns, a

nd e

nter

otyp

es e

nric

hed

with

Clo

strid

iale

s or

Prev

otel

la sp

ecie

s.20

7

Com

pare

d w

ith h

ealth

y co

ntro

ls, th

e st

anda

rdiz

ed m

ean

diffe

renc

es o

f Bifi

doba

cter

ia, L

acto

baci

llus,

Esc

heric

hia

Col

i, an

d E

nter

obac

ter

wer

e sig

nific

ant i

n C

hi-

nese

IB

S pa

tient

s.20

8

Usin

g lin

ear d

iscrim

inan

t ana

lysis

effe

ct si

ze m

etho

d, g

ut d

ysbi

osis

was

obs

erve

d in

subj

ects

with

IB

S (P

lesio

mon

as a

nd T

rabu

lsiel

la, e

ffect

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might be an effective treatment.124 However, studies of the gastric microbiota in FGIDs are still at an early stage.

The link between GI infection and FGIDs has been studied mainly in IBS. In 1994, a group in the United Kingdom reported that IBS frequently occurs in patients after Salmonella-induced enteritis.125 Thereafter, similar observations were reported world-wide, and a recent meta-analysis has clearly shown that IBS occurs frequently after bacterial enteritis caused by pathogenic strains of Escherichia coli, Salmonella, and Campylobacter jejuni.126 More-over, it is interesting that FD also occurs frequently in patients after bacterial enteritis, being compatible with the fact that IBS and FD often overlap in a single patient.126 After remission of bacterial enter-itis, no endoscopic and/or microscopic abnormalities are detectable in the GI tract of such FGID patients. Why, then, do patients with post-infectious IBS show visceral hypersensitivity and GI dysmotil-ity? Accumulating evidence has led to a hypothesis that pathogens disrupt the mucosal barrier and that subsequently mucosal immune cells are persistently activated as a result of increased exposure to luminal antigens.127 This low-grade mucosal inflammation is able to affect the immune system, endocrine cell behavior, and subsequent-ly visceral sensitivity and GI motility. This modification of the gut environment may be central to the development of post-infectious IBS.

As only about 10% of IBS patients have a history of infectious colitis,128 what is the role of gut microbiota in IBS patients without such a history? Recent advances in sequencing technology have made it easier to obtain information on gut microbiota at the genus level. Comprehensive analyses of fecal samples have demonstrated that the gut microbiota profile in IBS patients is largely different from that in healthy subjects, and has reduced diversity.99,129 Spe-cifically, several studies have demonstrated increased Firmicutes to Bacteroidetes ratios at the phylum level in IBS patients.99,129,130 At the genus level, Lactobacillus, Bifidobacterium and uncultured Clostridium are decreased in patients with IBS, whereas Rumi-nococcus species are enriched.130 Although it seems impossible to determine which bacterial strain is responsible for the development of IBS, dysbiosis of the microbiota is definitely a contributing factor. This is supported by experimental evidence that germ-free (GF) animals given microbiota transplants from IBS patients show vis-ceral hypersensitivity and GI dysmotility.131,132 On the other hand, although stress events in early life are closely associated with IBS development, the gut microbiota profile may be possibly modified by such events.133,134 Moreover, antibiotic-induced dysbiosis (espe-cially in childhood) has also been shown to be involved in the de-velopment of IBS.133,135 These findings suggest that events in early

life may be crucial in determining the IBS-related profile of gut microbiota. This invites speculation that manipulation of the gut microbiota may be useful for the treatment of IBS. Interestingly, the antibiotic rifaximin has been demonstrated to relieve the symptoms of IBS,136 although the mechanism responsible remains unclear. A meta-analysis has also indicated that probiotics may reduce IBS symptoms, although there was significant heterogeneity among the studies investigated,129,137,138 and the mechanism through which such probiotics act remains to be elucidated.

Possible Axis of Gut Microbiota and Enteroendocrine System Interaction in Functional Gastrointestinal Disorders Dysmotility

FGIDs are diagnosed on the basis of characteristic symptoms that are closely associated with food intake. The pathogenesis of FGIDs is multifactorial, and includes the neuroendocrine system, gut microbiota, neuroimmune reactions, interactions, psychological factors, and dietary factors.129 The complexity of FGID patho-physiology may be due to the fact that through their interaction, these factors may become a cause and/or a consequence of the pathophysiology. The physiological alterations in FGIDs are also complicated, but there is little doubt that GI dysmotility and visceral hypersensitivity are critical. Here, we would like to focus on the in-terrelationships existing among gut microbiota, gut hormones and GI dysmotility in FGIDs (Figure).

Enteric Nervous System ReceptorsThe enteric nervous system (ENS) in the GI tract comprises

a network of 200-600 million neurons and is involved in multiple aspects of host physiology including motility, metabolism, and be-havior. This neural network is arranged in distinct units between the longitudinal and circular muscle layers of the intestine or in the submucosa as ganglionated plexi.139 Gut microbiota may interact with the ENS directly or via afferent nerves (vagal sensory neurons, spinal sensory neurons and intrinsic primary afferent neurons) and the CNS indirectly through neurotransmitters. The link between microbiota and the ENS has been demonstrated in GF mice, which show a reduced number of enteric neurons and associated deficits of gut motility,140 whereas reconstitution of GF mice with conventional microbiota normalizes the density of the ENS network and, subse-quently, gut physiology.141

How, then, does the gut microbiota affect the ENS? Impor-tantly, the ENS expresses pattern recognition receptors known as

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Toll-like receptors (TLRs) by which the microbiota communicate with the host.142 Anitha et al140 have demonstrated that TLR4-deficient mice show a significant decrease of both the ENS network and GI transit time, and similar findings have been observed in TLR2-deficient mice.143 Another important ENS receptor type are the GPRs such as GPR41 and GPR43, which respond to SCFA signaling. Since the gut microbiota produce SCFAs, they can use them as chemical messengers or signaling molecules to communi-cate with the host ENS. At present, although little is known about a molecular alteration of the ENS by SCFA stimulation, treatment with butyrate enhances histone H3 acetylation in enteric neurons and increases the contraction of cholinergic-mediated colonic circu-lar muscle.144

Gut Microbiota, Immune System Activation, and Gastrointestinal Motility

Not only the direct but also the indirect action of gut micro-biota on the ENS is important, and this interaction is complicated. Microbiota-derived SCFAs play roles in the maintenance of intesti-nal barrier function,145,146 and indeed, butyrate, a microbiota-derived SCFA, prevents bacterial translocation by increasing the expression of tight junction proteins such as claudin, occludin, and the zonula occludens.147 In this context, it is interesting to note that in IBS pa-tients butyrate-producing bacteria may be reduced148 and intestinal permeability is increased.149,150 Thus, leakage of pathogens into the

lamina propria of the intestinal mucosa is a significant trigger for ac-tivation of the mucosal immune system. In IBS patients, increased amounts of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-8) and decreased amounts of the anti-inflammatory IL-10 have been reported.151 Th1 cytokines such as TNFα, IL-1β, and IL-6 may act on the ENS and smooth muscle, resulting in suppres-sion of GI motility.152,153 On the other hand, Th2 cytokines includ-ing IL-10 may inhibit the expression of the above cytokines, thus accelerating of GI motility.152,154 In IBS, it is still unclear whether these cytokines simply show this pattern of interaction. However, imbalance of not only gut microbiota but also the cytokine profile must be associated with intestinal low-grade inflammation, which is a significant pathophysiologic alteration in IBS.

Among the various immune cells, mast cells have been highlighted in the pathophysiology of IBS as their numbers are increased in colonic tissues of affected patients, and this increase is correlated with the severity of the clinical symptoms.155,156 Mast cells are able to release histamine, serotonin, tryptase, and prosta-glandins, and these mediators may act on their specific receptors on myenteric neural cells, leading to altered motor function.155 Recent evidence has emphasized the pivotal roles of macrophages in GI motility through their action on myenteric neural cells,152,153,157,158 and indeed increased infiltration of macrophages into colonic tissues is observed in IBS patients,156,159 implying that macrophages, like mast cells, may affect the ENS and smooth muscle through various

SCFA Medium-/long-chain FA

GPR40 GPR120TLRsGPR43GPR43GPR41

GLP-1 PYY 5-HT

Endocrine cell

Activation

Mast cell

GIP CCK,

GLP-1 PYY 5-HT

Macrophage

GLR-1RPYY-R

GPRsGIP-R

CCK-R

GPRs

TLRs

5-HT-R

ENS

GPRs

Gut hormone receptors

Microbiota

Cytokines

SCFAGut hormones

Figure. Interaction among gut micro-biota, enteroendocrine cells, immune cells, and enteric nervous system (ENS). SCFA, short-chain fatty acid; FA, fatty acid; GPR, G protein-coupled recep-tor; TLR, toll-like receptor; GLP-1, glucagon-like peptide 1; PYY, peptide YY; 5-HT, 5-hydroxytryptamine; CCK, cholecystokinin; GIP, glucose-depen-dent insulinotropic polypeptide/gastric inhibitory polypeptide; -R, receptor.

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mediators.152,153,157,158 Recently, macrophages have been classified into the M1 and M2 types that produce mainly Th1 and Th2 cyto-kines, respectively.160,161 Thus, M1 macrophages release proinflam-matory cytokines such as TNFα, IL-1β, and IL-6, whereas M2 macrophages may suppress M1 macrophages by releasing anti-inflammatory cytokines. Interestingly, M2 macrophages are known to infiltrate into the muscle layer of the intestine and may accelerate GI motility through stimulation with Th2 cytokines.155 Further-more, it has been reported that serotonin plays a role in polarization of macrophages toward an M2 phenotype.160,162 Supporting these findings, we have clarified that 5-HT expression is increased in the colon of GF mice after fecal transplantation, and that moreover M2 macrophages in the colonic muscular layer are increased in those mice.163 Furthermore, it is noteworthy that the numbers of muscularis M2 macrophages and 5-HT-positive endocrine cells are significantly correlated throughout the GI tract, and that their increase is associated with acceleration of GI motility. Thus, the gut microbiota plays a role in the association between accelerated GI motility and induction of the 5 HT/muscularis mannose receptor positive macrophage axis in the GI tract.163 Specifically, Muller et al164 have demonstrated that M2 macrophages migrating adjacent to the ENS may be involved in the control of GI motility through cross-talk with enteric neurons via bone morphogenetic protein 2 signaling.

Gut Microbiota and Gastrointestinal Motility-associated Hormones

The gut microbiota is able to affect GI motility via gut hor-mones. As shown in Tables 2 and 3, many investigators have inten-sively studied the gut microbiota and 5-HT in patients with IBS. However, to clarify the role of gut microbiota in the gut hormone/GI motility axis in IBS, experimental animal studies are needed. In particular, much evidence has been obtained from experiments us-ing GF animals. For example, Wikoff et al165 first demonstrated that GF mice display lower levels of 5-HT than conventionally raised animals, suggesting that the presence of gut microbiota is essential for the production and release of 5-HT.165 In addition, Kashyap et al166 have clarified that colonization of GF mice with gut micro-biota from humans or mice can significantly shorten the GI transit time and that this effect is partially inhibited by 5-HT receptor antagonist.166 These findings strongly indicate that 5-HT induced by microbiota stimuli play a role in the acceleration of GI motility. Moreover, Yano et al167 have clarified that indigenous spore-forming bacteria from the gut microbiota promote tryptophan hydroxylase 1 expression and 5-HT biosynthesis in EC cells, thus modulating

GI motility. Although the mechanism by which microbiota induce 5-HT expression is still unclear, SCFA and cytokines in minimal inflammation may be candidate stimuli for 5-HT-producing EC cells,168 and the microbiota themselves may also produce 5-HT.101 On the other hand, various types of 5-HT receptors are present on not only central and peripheral neural cells but also immune cells, smooth muscle, and enterocytes.168,169 Additionally, the SERT, which terminates the action of 5-HT, is expressed in epithelial cells, neural cells, and platelets.169 Accordingly, it is extremely difficult to determine how the gut microbiota/5-HT axis operates in GI motil-ity and the development of symptoms in FGIDs.

Recently, not only 5-HT but also other gut hormones have been highlighted in relation to the gut microbiota/gut hormone axis in GI motility. As a result of their elegant work, Wichmann et al113 have proposed that the microbiota/GLP-1 axis is important for regulation of energy availability and GI motility. Specifically, entero-endocrine L cells sense the amount of bacteria-producing SCFA in the colon and secrete GLP-1 to allow greater nutrient absorption by inhibiting intestinal motility. Accordingly, it is tempting to speculate that GPR41 and GPR43 may play some roles in this process be-cause these receptors are responsive to SCFA ligands. In support of this hypothesis, in vitro studies have shown that the SCFA affects GLP-1 secretion via GPR43 and/or GPR41 in L cells.111,170 En-teroendocrine cells are significant intermediates in facilitating com-munication between microbes and the ENS.171 By using GF with fecal transplantation animal models, we have recently demonstrated that gut microbiota accelerate GI motility while suppressing the ex-pression of the GLP-1 receptor in myenteric neural cells through-out the GI tract.172 These findings suggest that the gut microbiota affects the expression of gut hormone receptors on the ENS in the GI muscle layer.

Except for 5-HT and GLP-1, there are few data on the role of the gut microbiota/gut hormone axis in GI motility. As PYY is produced in L cells, it may––like GLP-1––be a sensor for SCFA and inhibit GI motility. Interestingly, GPRs are widely expressed in enteroendocrine cells such as those producing ghrelin, CCK, GIP, PYY, or GLP-1.170 Moreover, since enteric neurons harbor the receptors for all of these gut hormones, a mechanism similar to that for GLP-1 or 5-HT may exist in the microbiota/gut hormone axis to mediate GI motility.

Summary and Conclusions

Gut microbiota have a pivotal influence on various functions including GI motility, metabolism, nutrition, immunity, and the

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neuroendocrine system in the host. This variety of bacterial actions is due to the production of SCFA and various mediators such as gut hormones and/or cytokines, which gut microbiota induce in en-teroendocrine and immune cells. Moreover, the receptors for SCFA and gut hormones are widely distributed in neural cells, endocrine cells, immune cells and smooth muscle, further making it difficult to understand the role of gut microbiota in the pathophysiology of FGIDs. GI motility is well orchestrated by the ENS and hormonal networks, and its disturbance is closely associated with not only GI dysmotility but also visceral hypersensitivity and energy imbalance, that are significant abnormalities in the pathophysiology of FGIDs. In this article, we have mentioned that the gut microbiota may af-fect the ENS directly via the SCFA, or indirectly via gut hormones. Furthermore, we have described that gut microbiota elicit minimal inflammation by activation of the immune system and that mast cells and macrophages modify GI motility by acting on the ENS and smooth muscle. In this context, alteration of the gut microbiota/gut hormone axis significantly affects GI motility in the pathophysi-ology of FGIDs.

Although we have focused on GI motility in FGIDs, both the gut microbiota and gut hormones also play pivotal roles in metabo-lism, the brain-gut axis, and systemic immunity. Interestingly, the gut microbiota and gut hormones have been highlighted as targets of new therapeutic approaches for FGIDs, and indeed some trials using probiotics, antibiotics or gut hormone agonist/antagonists have been undertaken. Also, fecal microbiota transplantation, as applied to Clostridium difficile infection, may be attempted for FGIDs in the future. The research field focusing on interactions between gut microbiota and gut hormones may be referred to as “microbial endocrinology,” and is expected to become a focus of intense interest in the near future.

Financial support: None.

Conflicts of interest: None.

Author contributions: Hirokazu Fukui and Xin Xu drafted the manuscript and constructed Tables and a Figure; and Hiroto Miwa coordinated the study and performed critical revision of the manuscript.

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Role of Gut Microbiota-Gut Hormone Axis in the ... · Role of Gut Microbiota-Gut Hormone Axis in the Pathophysiology of Functional Gastrointestinal Disorders Hirokazu Fukui,1* Xin

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